Background and aims: Autophagy is a critical process in cell survival and the maintenance of homeostasis. However, the implementation of therapeutic approaches based on autophagy mechanisms after liver damage is still challenging.
Methods: We used a hepatospecific Atg7-deficient murine model to address this question.
Results: We showed that the proliferation and regeneration capacity of Atg7-deficient hepatocytes was impaired. On the one hand, Atg7-deficient hepatocytes showed steady-state hyperproliferation. On the other hand, external triggers such as partial hepatectomy (PHx) or cell transplantation did not induce hepatocellular proliferation or liver repopulation. After PHx, hepatocyte proliferation was strongly decreased, accompanied by high mortality. This increase in mortality could be overcome by pharmacological mTOR inhibition. In accordance with hepatocyte hypoproliferation after damage, Atg7-deficient hepatocytes failed to repopulate the liver in a hepatic injury model. Atg7-deficient mice showed hepatic hypertrophy, transient cellular hypertrophy, and high transaminase levels followed by strong perisinusoidal/pericellular fibrosis with age. Their elevated modified hepatic activity index (mHAI) was almost exclusively due to apoptosis without any inflammation. These parameters were associated with variations in the triglyceride content and compromised lipid droplet formation after PHx. Mechanistically, we also observed a modulation of HGF, PAK4, NOTCH3 and YES1, which are proteins involved in cell cycle regulation.
Conclusion: We demonstrated the important role of autophagy in the regeneration capacity of hepatocytes. We showed the causative relationship between autophagy and triglycerides that is essential for promoting liver recovery. Finally, pharmacological mTOR inhibition overcame the impact of autophagy deficiency after liver damage and prevented mortality.
Keywords: Atg7; Autophagy; lipid droplets; liver regeneration; mTOR; partial hepatectomy; transient hepatic steatosis; triglyceride.
© 2020 The Authors. Liver International published by John Wiley & Sons Ltd.